Various investigations have been hitherto made on drug carriers for improving delivery of a drug contained therein from the bloodstream or an applied site to a lesional tissue. For example, a method is known for utilizing liposome prepared with a phospholipid incorporated therein ("Drug Carriers in Biology and Medicine" (1979), Ed. by G. Gregoriadis, Academic Press).
According to this method, however, defects are encountered in that there are problems in the stability of liposomes enveloping an aqueous phase with a lipid bilayer during its storage and in the case of administration into blood, almost all liposomes are taken up into tissue with a developed reticuloendothelial system (RES) such as liver, spleen, etc. so that they are difficult to distribute to other cells or tissues, etc. This is believed to be the case since liposomes have a structure wherein the inner and outer aqueous phases are separated from each other by a phospholipid bilayer and the liposome is thus unstable to various forces. An increase in particle diameter due to aggregation is another known defect during its storage.
According to investigations in recent years, a technique is known in which various drugs are dissolved in a fat or fatty emulsion having a particle diameter of 0.2 .mu.m and composed of soybean oil and yolk lecithin heretofore used clinically as a fluid supplementation for purposes of nutrient supplements when the solution is used and good results are thereby obtained according to the invention as described above (SAISHIN SGAKU (Latest Medicine), 40, 1806-1813 (1980). This carrier is characterized in that it has no internal aqueous phase and can be extremely well stored with stability as compared to liposomes.
However, the carrier of the invention has a property that is readily and rapidly taken up into the aforesaid reticuloendothelial system such as the liver, etc. Such a rapid metabolism is desired as a calorie fluid supplementation but involved problems of causing poor distribution of a drug into other tissues as a drug carrier adapted for the object described above, etc. and was not necessarily desirable.
Further, the concept of using fat or a fatty emulsion whereof 90% is 100.+-.30 nm as a carrier for pharmaceuticals is disclosed in Japanese Laid Open Application 63/500456. However, preferential accumulation on the reticuloendothelial system such as liver and spleen occurs and, as already described, raises a problem in the delivery of a drug to other tissues.
It is most important in the transfer of drugs to the infection focus in other parts of the body that the drug carrier avoid incorporation into the reticuloendothelial system. Development of just such drug carriers having this property have been awaited. In particles having a size distribution of 100.+-.30 nm, it is apparent that most of the drugs therein are present in sizes not less than 100 nm. This can be easily calculated by the fact that the volume of a particle is proportional to the cube of its diameter and it shows that drugs existing in particles are mostly distributed to the side of particles of bigger size. This results in substantial transfer to the liver (i.e. reticuloendothelial system) causing the above-mentioned disadvantage.
As a means for solving the foregoing problems, a technique of applying serum lipoproteins composed of a simple lipid (including sterols, as described in the present specification), a complex lipid and an apolipoprotein as a drug carrier is known (Japanese Patent Application Laid Open No. 60-163824). However, the purpose of this carrier is to introduce a drug into cells by physiological and specific recognition of the lipoprotein. Therefore, the carrier is rapidly transferred into the tissue via its receptor so that disappearance from the blood is relatively rapid. For this reason, transfer into a tissue having a poor receptor activity is not always sufficient. Furthermore, an apolipoprotein is indispensable as a constituent so that the technique is subject to a defect in industrial technique that results in high production costs.
Further, all attempts to make a fat emulsion of 200 nm particle size more fine is known (cf. Japanese Laid Open No. 62/29511). However, in this art, yolk lecithin is infrequently used and, accordingly, the resulting microparticles are recoagulated only after a time lapse resulting in a problem of instability. Moreover, there is a disadvantage with respect to the stability in vivo, so this procedure is not desirable in terms of successful delivery of active therapeutic agents to other tissues.
The present invention provides for a composition useful for improved drug delivery upon administration, which comprises a core comprising a lipophilic substance and a surface covering for the core, wherein one of the core or a part thereof or the surface covering or a part thereof comprises the drug to be administered and the other comprises a carrier therefor, the carrier having a particle diameter not less than 10 nm up to 100 nm and wherein the carrier is selected from the group consisting of compound lipids, simple lipids and derived lipids and the drug is present per se or in the form of a lipid mixture, the composition comprising 30% to 65% core and 35% to 70% surface covering.